Improving MPS I ERT Efficacy through Lectin-Mediated Delivery

该项目的长期目标是通过以下创新为MPS I患者开发改进的ERT 在整合的同时加强ERT的传输和脑等难治器官的疾病纠正 植物性生物生产的安全性和成本优势。MPS I综合征是由遗传因素引起的 溶酶体酶α-L-艾杜糖酸酶(IDUA)缺陷。虽然目前针对MPS的ERT药物选择是 有效治疗多脏器，本病在中央有明显的衰弱表现 神经系统(CNS)仍有待解决。BioStrategy之前的细胞研究表明， 这种凝集素对哺乳动物细胞表面常见的糖蛋白和糖脂具有很高的亲和力， 可以介导有效的细胞摄取、跨细胞作用和IDUA向溶酶体的输送。体外分析 在MPS I患者成纤维细胞中，我们的IDUA-凝集素融合(简称IDUA融合)显示出快速和 有效纠正细胞疾病表型。我们对该项目的第一阶段可行性动物研究 已经表明，身份可以被传递到MPS I小鼠模型动物的大脑中 纠正了这种疾病的细胞和行为表型，并实现了里程碑 第一阶段研究的目标。这一后续第二阶段提案的具体目标是：1)体内评估 在MPS I小鼠中的药物剂量水平、频率和中枢神经系统药物传递和疗效读数，2)发展 支持高级临床前研究的单独产品扩展、稳定性和鉴定协议，以及 3)建立严格的临床前动物数据，评估疗效、治疗开始年龄、免疫原性、 长期服药后的性别影响和行为矫正。 实现该项目的第一阶段目标，显示在体内的细胞和行为动物效果 IDUAL为我们的凝集素载体ERT融合给药技术提供了关键的概念验证。 这一第二阶段更新项目的总体目标将是完成下一阶段的药物生产 规模扩大，高度严格的动物研究，将为后续的临床前研究奠定坚实的基础 支持启动临床试验的IND申请成功所需的研究。 我们对该项目的成功概念验证研究的进一步深入将为潜在的 这种基于凝集素的药物传递技术平台在以前的各种其他方面的应用 难以治愈的疾病。

The long-term goal of this project is to develop an improved ERT for MPS I patients with innovations that enhance ERT delivery and disease correction in hard to treat organs such as the brain while integrating safety and cost advantages of plant-based bioproduction. MPS I Syndrome is caused by genetic deficiencies in the lysosomal enzyme α-L-iduronidase (IDUA). While current ERT drug options for MPS I effectively treat many visceral organs, significant debilitating manifestations of this disease in the central nervous system (CNS) remain to be addressed. Previous cellular studies by BioStrategies showed that this lectin, which has high affinity for glycoproteins and glycolipids common on mammalian cell surfaces, can mediate efficient cellular uptake, transcytosis, and delivery of IDUA to lysosomes. In vitro analyses of MPS I patient fibroblasts treated with our IDUA-Lectin fusion (termed IDUAL) demonstrated rapid and efficient correction of cellular disease phenotypes. Our Phase I feasibility animal studies on this project have shown that IDUAL could be delivered to the brains of MPS I mouse model animals yielding correction of both cellular and behavioral phenotypes of this disease and achieving the milestone objectives of the Phase I study. Specific aims for this follow-up Phase II proposal are 1) Assess in vivo drug dosage levels, frequency, and CNS drug delivery and efficacy readouts in MPS I mice, 2) Develop IDUAL product scale-up, stability, and qualification protocols to support advanced preclinical studies, and 3) Establish rigorous preclinical animal data assessing efficacy, age at treatment onset, immunogenicity, gender effects, and behavioral correction following long-term IDUAL administration. Achievement of phase I goals of this project showing in vivo cellular and behavioral animal efficacy of IDUAL has provided a critical proof-of-concept for our lectin carrier ERT fusion drug delivery technology. The overall goal of this Phase II renewal project will be to complete the next stage of drug production scale-up, and highly rigorous animal studies that will lay a solid foundation for the follow-up preclinical research that will be required to support a successful IND application for initiating clinical trails. Furtherance of our successful proof-of concept studies on this project will build a solid basis for potential applications of this lectin based drug delivery technology platform to a wide variety of other previously hard to treat diseases.